Abstract 272: Effect of inositol hexaphosphate on cancer stem cell pool of prostate tumors

Abstract

Abstract Prostate cancer (PCa) is the most frequently diagnosed invasive malignancy and second leading cause of cancer-associated deaths in the males in the United States. Inositol hexaphosphate (IP6) a nutrient constituting 6.4% (w/w) or even higher levels in most cereals, legumes, nuts, oil seeds and soybean has been shown to protect against growth and progression of PCa in pre-clinical animal models. Our completed studies in a spontaneous transgenic mouse model of PCa (TRAMP) have shown that IP6 feeding suppresses growth and progression of PCa via its ability to alter tumor vascularity and the energy generating metabolic events in the tumor cells. We also employed quantitative high-resolution nuclear magnetic resonance spectroscopy (1H-, 13C- and 31P-NMR) to assess the metabolic profile and energy state of the IP6-treated human PCa PC3 cell line which validated these in vivo findings. Next, we assessed stage-specific efficacy of IP6 feeding on PCa initiation and growth, progression and angiogenesis, and elucidated the molecular events involved in IP6 effects during these stages. Different groups of male TRAMP mice starting at 4, 12, 20 and 30 weeks of age were fed with regular drinking water or 2% IP6 in regular drinking water for 8-10 weeks. Study end point assessments showed that IP6 treatment results in arrest of tumor grade at earlier stages and prevents its progression to more advanced forms of the disease. In more recent studies, to determine whether these protective effects are mediated via the effect of IP6 on expansion of cancer stem cells (CSCs) pool; we next assessed whether IP6 had the potential to affect the CSC pool in TRAMP prostate tumors. We observed that the anti-PCa effects of IP6 are associated with its potential to eradicate PCa CSC pool, which is recognized to be involved in the initiation, progression, relapse, and therapy-resistance of PCa. IP6 feeding also showed inhibitory effects on the CSC associated transcription factors and signaling pathways. Next, we performed in vitro sphere cluster assays to determine IP6 effect on the self-renewal capacity of the CSCs of PCa cell lines PC3 and HMVP-2. The % of floating spheroids (prostatospheres) generated in the presence of macrophage U-937 conditioned media (with and without IP6 pre-treatment) after 1-2 weeks were determined. The results indicated an inhibitory effect of IP6 on both number and size (volume) of prostatospheres. Since formation of spheroids under specific in vitro conditions is a measure of stemness, it is evident that IP6 has the potential to target the self-renewal of CSCs in PCa cell lines. Since these mechanistic events eventually result in arrest of tumor grade at neoplastic stages, this protective effect of IP6 against PCa might have clinical implications in controlling the malignancy at an early stage. Together, these findings suggest the practical and translational potential of IP6 treatment in suppressing growth and progression of PCa in humans. Citation Format: Komal Raina, Anil K. Jain, Dileep Kumar, Vijay Mohan, Paul Maroni, Rajesh Agarwal. Effect of inositol hexaphosphate on cancer stem cell pool of prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 272.